Adducts of 9,11-oxido-5,7-pregnadien-3,20-dione



Patented Nov. 11, 1 95 2 UNITED STATES PATENT GFFICE ADDUCTS F9,11-OXlfiO-BJ-PREGNADTEN- sen-moms Robert H. Levin, A Vern McIntosh,Jr., and

GeorgeB. Spero, Kalamazoo, Mieh., assignors to The UpjohnCompany,-Kalamazoo, Mich., a corporation of Michigan No" Drawing.Application Aligilst' 23"; 1950;

Serial No. 181,111

The present invention mates: td'ddiitsbf 9,11=oxido5,7-pregriadien=3;20=dione with cer tai'n' dienophilic acids,anhydrides'; and esters; and

to a process for the productiori'the reoi The'compounds-ofthepresentinveiitioh'maybe represented by the structural -"f l/ wherein Ais an adduct radicabderivedfrohi a dienophile selecte'cl from the groupconsisting ofmaleic acid,malei'c anhydride, arid 'rrialeic acid diesterscontaining 'from'one toeight carbon atoms, inclusive, in the esterifyinggroup;

It is an object ofthe present invention to providea novel group ofoompounds' which 'are"use'- ful in the preparation of steroidconipbun'dscontaining an oxy en "atom at carbon atom eleven.

Another object or the invention is the provision of a 'prbcess ro r theproduction time novel com-' 3,20-dione. Other objects fflih inventionwill become appa'rent hereinafter; v

The compounds of the" present invention} as previously stated, areuseful inthepreparatioh of steroid compoundsha'virig an oxygenatomattached to carbon atoifi ele en; Such are or particular inter'sti inthe-{field oi steroid research due to the biological activity of thecortical hormones and certain known-derivatives thereof, whichoxygenated; steroids are known to have biological effects differingmarkedly from" the unoxygenated steroidsr It isptherefore, of

importance to investigate theokygenatedderivatives of such a'dduct's-yas Well"astheir transfer-met tion products'a I "d by the acute""ca r brme'nee; an'd 'the absence of anyf present "suggestion foralleviation of the saidshortage excepfi 'through "organic synthesis; I

N ovel" compounds of the prese'nt invention which are- Of particular"1111; Est '91! those dofil pounds" of the" sewage c" wherein b'e'n'yland likelesters;

ducts of th'riresnt invention are prefiar e d by' 9' claims. (01.260-23955) the adduct bridgef( A-) is represented by the graphicformula: V

wherein R represents matte" for thef' o rganic residue of an'alcohol.Sue sters inolude the methyl, ethyl; 'propyl," isopr' yl, bu ty'l,isobutyl, laurylf heiotylj oc'tyl, cycl cy'clohexyl, The estnd ngradical may also contain non-reac "ve substituents; such asihalofi mi1i6 $Q fihY f 2 ii sirf W le the esters of the rnaleic acidaddi ct' aredescribed herein with partic ar"refe r'e'nce to the methyl esters,th'e'preferred fe odiment or R is a 1ew'ralkyl radical cont'aining fromf "oneto: eight carbon' stasis; memes Alternatively, the ja'dauet may beeri'ibtd were graphic formula:

which is representative of the maleic anhydride adduct.

The compounds of the invention are usually colorless crystalline solids.The acid anhydride adduct is readily converted to the acid adduct 1 byhydrolysis. The acid adduct in turn is readily nt th annyariqe either byheat wherein A has the value previously assigned. These 3-hydroxyadducts are in turn prepared from 3-substituted-5,7,9 (1 1)-pregnatrien-20-one adducts, having the formula:

wherein B is selected from the group consisting of hydroxy and anacyloxy group derived from an organic carboxylic acid containing fromone to ten carbon atoms, inclusive, and A has the value previouslyassigned. In such compounds, B represents either hydroxy or an ester ofthe 3-hydroxy group with a carboxylic acid containing up to andincluding ten carbon atoms. Among the acids which can be used areformic, acetic, propionic, butyric, valeric, hexanoic, heptanoic,octanoic, decanoic, succinic, glutaric, cyclopentanoic, benzoic, toluic,and the like. Preferred acids are those containing from one to eightcarbon atoms, inclusive, and especially such lower-aliphatic acids. Theacids may also contain substituents, such as halo, alkyl, and methoxy,which are non-reactive under the reaction conditions employed. The3-hydroxy compounds are prepared from the 3-acyloxy compounds bysaponification, which procedure is productive of the 3-hydroxy ketonediacid, which can then be converted to the anhydride or diester ifdesired, as more fully described hereinafter.

The 3 substituted 5,7,9(11) pregnatrien- 20-one adducts are convenientlyprepared by the selective oxidation of an enol ester of an adduct of 3acyloxybisnor 5,7,9(11) chlolatrien 22-al. represented by the formula:

CHa

wherein A and B have the values previously given, B in this caseexcluding the free hydroxy group.

Adducts of 3,22-diacycloxybisnor-5,'7,9 (l1) 20 (22) -chlolatetraenes'[22-enol esters of 3-acyloxybisnor-5,7,9(11)-cholatrien-22-a1sl areconveniently prepared by subjecting an adduct of a 3 acyloxybisnor5,7,!)(11) cholatrien 22 al, of the formula:

CH-CHO CH3 wherein A and B have the values previously given, to theaction of an acid anhydride or an acid halide in the presence of analkaline salt of the acid. The starting adducts of 3-acyloxybisnor-5,7,9(11) -cholatrien-22-als can be prepared from adducts of 3-esters ofdehydroergosterol by selective oxidation as described and claimed in thecopending application Serial 111,100 of Robert H. Levin, filed August18, 1949, and as more fully described hereinafter. I

The 3-esters of dehydroergosterol, from which the 3-acy10Xybisnor-5,'7,9(11) -cholatrien-22-al adducts are prepared, can be synthesized inseveral ways starting with ergosterol. For example, ergosterol can betransformed to dehydroergosterol with mercuric acetate according toknown methods [Windaus et al.,. Ann. 465, 157 (1928)] and the B-hydroxygroup of the dehydroergosterol acylated by known procedure.Alternatively the B-hydroxy group of ergosterol can be acylated prior tothe preparation of the dehydro derivative, a procedure which isparticularly preferred in the preparation of the 3-acetoxy derivative.The adducts of dehydroergosterol are then prepared by the addition ofmaleic anhydride or the like to dehydroergosterol or a 3-ester thereofaccording to known methods [Honigmann, Ann. 508, 89 (1934)]. Theanhydrides can then be converted to their corresponding acids and estersif desired.

The ester group, when present in the 3-position of dehydroergosterol, isfor the purpose of protecting the 3-hydroxy group in subsequent chemicalreactions. For this purpose any convenient ester of an organiccarboxylic acid, which is nonreactive under the conditions of thereaction, is suitable. The preferred acids are the fatty acids such asformic, acetic, propionic, butyric, Valerie, hexanoic, heptanoic,octanoic, decanoic; dibasic acids such as malonic, succinic, phthalic;cycloaliphatic acids such as cyclopentanoic and cyclohexanoic;'andgaromaticacids such as benzoic, toluic, naphthoic, and the like. Theacids may also contain substituents such as halogen, alkyl, the methoxyradical, and the like, and these substituents will be carried throughoutthe synthesis. If desired, the acyl group can be changed to another acylgroup by saponifying the ester to give a 3-hydroxy compound,-which canthen be reesterified as previously described.

A preferred method for preparing some of the dehydroergosteryl adductscomprises the saponification of a 3-acyloxy-adduct of dehydroergosterolwith dilute alkali followed by acidification. The S-hydroxy dicarboxylicacid thus formed can be converted to the 3-hydroxy anhydride by heat, orit can be converted to any desiredS-acyloxy anhydride adduct by heatingunder reflux with the appropriate acid anhydride or chloride in pyridinesolution. Dialkyl, esters of the previously mentioned dicarboxylic acidadducts can be presulfonic or sulfuric acid. hydride is aceticanhydrida'but other anhydrides,

J pared by subjectingme acid tb-Ltheab'tion of an esterification reagentsuch as diazometha'ne; diazoethane, diazobuta'neg" and the like.

The selective oxidation-of an addiict of' dehydroergosterol, or a -3-ester thereof, to produce an adductof 3-hydroxybisnor 5 911)-"-cholatrien-22-al, or 1 a 3-ester thereof, =isaccomplished erablybetween a temperature 'of minus'30: and minus 'io degrees centigrade,during the addition of ozone, although temperatures as-lowas minus 8.0and as high as plus-30 degrees centigradeare operative. The-lowertemperatures of-thepreferred range are readily obtained-bycooling thesolution of the adduct with abath-of solid carbon dioxide in acetone orthe like, althoughvarious other methods of cooling-can be used; Many ofthe customary solvents used in ozonizations 'such as chlorofor-rn,-acetic acid, carbon tetrachloride, ethylene chloride, -methylenechloride,

and the like, can be-used.

-' The ozonides are. then .decomposed under reducing conditions that-is,--in theabsence of oxi- 'dizing agents, whether added or formed'in thecourse of the reactionby products of decompositionof the ozonide. Thismeansthat excess oxygen formed-by decomposition of the ozonide isprevented from forming'hydrog'en peroxide by combining with any moisturepresent, andthat molecular oxygen isprevented from oxidizing thealdehyde thus formed. This can be conveniently accomplished bydecomposing the ozonide in glacial acetic acid by the addition of'finelypowdered zinc.

As is conventional with ozonizations when conducted in solvents,otherthan glacial acetic acid, the solvent used for ozonization isreplaced, after completion -ofthe ozonization, by adding glacial aceticacid and removing the lower-boiling solvent by fractional distillation.Alternatively, the solvent can be removed by careful warming underreduced pressure prior to the addition of glacial acetic acid, ifdesired.

After decomposition of the ozonide and removalof the zinc,- the'aldehydecan berecovered "by diluting the acetic acid with-water, or in otherconventional manner, such as by formation of analdehyde derivative, e.g., the dinitrophenylhydrazone.

Adducts of 3-substituted 22-acyloxybisnor- 5,7,9 11) 20 (22)-cholatetraenes- [22-enol-esters of adductsof3-acyloxybisnor-5,7,9(11)-cholatrien-22-als] can be convenientlypreparedby of-"the acid corresponding to'the anhydride employed oran-acid catalyst such as para-toluene The preferred ansuch as propionic,butyric, valeric, hexanoic, and

octanoic, and-,decanoic anhydrides,. as Well as benzoic acid anhydride,IOIthOetOllllC acid anhydride, naphthoic acid anhydride, and the like,

' are also 'operative; J The. acid'janhydride's c'analso \Ebeisub'stituted by -non-r'eactive'- groups, such as --ha'lo, alkyly-andmethoxmas the case of I actionmixture, optimum yields-being obtained bydiscontinuing I. the application of heatwhen 'the color of the solutionchanges from yellow-to brown. Ordinarily the -reactionis-heat'ed atabout 140 degrees centig-rade for 'fromaboutfour to sixhours,---butitemperaturesas low as 100 and as high as 180 degreescentigrade are also operative. -"I hereaction is usually-conducted atthe *tions, such as chloroform; methylene-chloride,

of the higher-boiling-anhydrides,such asbenzoic anhydride, a suitabletemperature control, such as degr'ees =centigrade, must .beused, -sincethe: adduct otherwise-tends to decompose in the higher-temperaturerange/ 1f a 3-hydroxy aldehyde adduct is" thus--reacted-withan an- Ihydride, thehy'droxy group will beacylated-,--and, similarlyyif a maleicacidadductis used instead of a--diester on an anhydri'de, the anhydridewill beformed. The enol estercan be isolated byremoving the-excess:anhydrideunder reduced-pressure, and separating the-enol ester from-alkali metal salts, which procedure yields a product suficientlypure-for most purposes; but'which can be further purifiedby-recrystalization from *Loss to the'solvent, if any loss-occurs, must betaken into considerationin calculating-- the amount of ozone to beintroduced. The temperature'of the solutionshould be maintainedbelowplus thirty-degrees centrigrade; preferably'between atemperature'ofminus'thirty-and minus seventy degrees centigrade, 1 during the additionof ozone although temperatures as 'lowas minus eightyand as high as plusthirtydegrees centigradeare operative. The lower temperaturesof therange are readily obtainedby cooling the solution of the adduct withabathof-solid'carbon dioxide in-acetone orthe like, although variousother methods of cooling-may be employed. Many of the customary"solvents used inozonizaethylene chloride, carbon tetrachloride, aceticacid, and the like, can be used for the ozonization reaction.

The 20:22 "'ozonides thus produced are then decomposed underconditionsnormally employed forv decomposition of-such compounds. This can beaccomplished conveniently. by decomposing the ozonide withhydrogenperoxide, by hydrolysis, with zinc in glacial-aceticacidyor byacata'lytic amount .of colloidal metal such as silverypliitinum, ,orpalladium in a, solvent; such as glacial ductive conditions is wellestablished in the art [Hill and Kelly, Organic Chemistry, page 53, theBlackiston Company, Philadelphia (1934); Churchet al., J. Am. Chem. Soc.56, 176484 (1934); Gilman Organic Chemistry, second edition, page 636,John Wiley and Sons, New York (1943); Long, Chem. Reviews 27, 452-454(1940)].

As is conventional with decomposition of ozonides with zinc, when theozonizations are conducted in solvents other than glacial acetic acid,the solvent used for the ozonization is replaced, after completion ofthe ozonization, by adding glacial acetic acid and removing thelower-boiling solvent by fractional distillation, or the solvent can beremoved by careful warming under reduced pressure prior to, the additionof acetic acid, if desired. After decomposition of the 20:22 ozonide andremoval of the metal, the ketone can be recovered by diluting the aceticacid with water, or by other conventional procedure for the recovery ofketones, such as by formation of a carbonyl derivative, e. g., the2,4-dinitrophenylhydrazone. Recrystallization from acetone or the likeresults in a more highly purified ketone product. The 3-hydroxy ketonesare prepared by saponification of the 3-acyloxy group to give the3-hydroxy ketone diacid, which can then be converted to the anhydride ora diester, if desired, by heating in a vacuum or by reaction with adiazoalkane respectively.

The preparation of the 3-hydroxyor 3-acyloxy-9,1l-oxido-5,'7-pregnadien20 one adducts involves the oxidation of the corresponding 3- hydroxyor3-acyloxy-5,7,9(l1) -pregnatrien-20- one adduct using an organic peracidor concentrated hydrogen peroxide as the oxidant. Hydrogen peroxide isusually employed in the form of a twenty to ninety percent by weightaqueous solution, a thirty percent solution being preferred. Thereaction is carried out by stirring the adduct and oxidant together,preferably in an or anic medium which is non-reactive under the reactionconditions. Suitable media include chloroform,

carbon tetrachloride, mixtures of ether and chloroform, glacial aceticacid, and many others. Theratio of oxygen-furnishing agent to steroidcan be varied considerably within broad ranges. Ratios of up to twentymoles to one are operative, but ratios of from one to four moles permole of steroid are preferred for attainment of optimum yields, theexact ratio being preferably varied inversely with the reaction timedesired to be employed. The temperature of the mixture is usuallymaintained at from about zero degrees to about 100 degrees centigradefor a suitable period, c. g. from about one-half to twenty-four hours,depending on the concentration of oxygenfurnishing agent, and the9,1l-oxido compound then isolated in any convenient manner, such as byvolatilizing the reaction medium, extracting the residue withchloroform, filtering, volatilizing the chloroform, and recrystallizingthe residue, e. g., from eighty percent aqueous acetone. Alternatively,the compounds may be recovered by pouring the reaction product intowater, filtering the solution, and drying the precipitate. The9,1l-oxido compound is usually obtained in a state of high purity afterone or two recrystallizations. A convenient reaction medium when theoxidant is hydrogen peroxide is glacial acetic acid, and, when such isemployed, the 9,11-oxido compound is separated readily by pouring thereaction product onto cracked ice to precipitate the 9,11-oxidocompound, filtering, and recrystallizing the dried crude product, e. g.,from ethyl acetate.v The 3-acyloxy 9,11-oxido compounds, when such areprepared from corresponding S-acyloxy- 5,7,9(11)-pregnatrien-20-ones,are readily convertible to the 3-hydroxy compounds by saponificationwith a base, which procedure is productive of the 3-hydroxy diacid,which can then be converted to the B-hydroxy anhydride by heat in avacuum, or to the 3-hydroxy diester by treatment with diazomethane,diazoethane, or the like.

The 9,11-oxido-5,7-pregnadien-3,20-dione adducts of the presentinvention are prepared by the controlled oxidation of the corresponding3- hydroxy compound to convert the B-hydroxy group therein to a ketogroup. This is conveniently accomplished by mixing the selected maleicanhydride, maleic acid or maleic acid diester adduct of3-hydroXy-9,l1-oXido-5,7-pregnadien-ZO-one with from one to four molarequivalents of chromic acid, from one to a slight excess over oneequivalent being preferred. The reaction is conducted in an acetic acidmedium, in the presence of a catalytic amount of sulfuric acid. Thetemperature at which the reaction is conducted is between about sixteenand twentysix degrees centigrade, which is conveniently maintained bycooling the reaction in a water bath while adding a mixture of chromiumtrioxide, a small quantity of water, acetic acid, and a catalyticquantity of sulfuric acid dropwise to a solution of the B-hydroxycompound in acetic acid. The reaction is conveniently followed byobserving the color change of the chromic acid. Upon completion of thereaction, the product is recovered in conventional manner, such as bydrowning out by the dropwise addition of water to the reaction mixture.If desired, the product may be recrystallized from ethyl acetate,acetone, or like solvents, to give a more highly purified product.

An especially preferred procedure for recovery of the keto diacidinvolves dissolving the reaction product in a base, e. g., sodiumhydroxide, carefully acidifying with dilute hydrochloric acid, andcooling the resulting mixture to cause precipitation of the crystallineproduct.

The following examples are illustrative of the process and products ofthe present invention, but are not to be construed as limiting.

Prepamtion 1.D2mefhyl maleate adduct of dehydroergosteryl benzoate To asolution of 21 grams of dimethyl maleate adduct of dehydroergosterol in69 milliliters of warm pyridine was added 9.5 milliliters of benzoylchloride. After standing at room temperature for fifteen minutes, themixture was poured into 1400 milliliters of ice-water and the solidremoved by filtration, dried, and recrystallized from acetone. There wasthus obtained 26.4 grams of dimethyl maleate adduct of dehydroergosterylbenzoate, melting at 203 to 205.5 degrees centigrade.

Preparation 2.Dimethyl maleate adduct of dehydroergosferyl acetate In amanner essentially that described in Preparation 1, the dimethyl maleateadduct of dehydroergosteryl acetate, melting at 177 to 179 degreescentigrade, was prepared from the dimethyl maleate adduct ofdehydroergosterol and acetyl chloride.

Preparation 3.Dimethyl maloate adduct of dehydroergosteryl formate Asolution of six grams of dimethyl maleate adduct of dehydroergosterol infifty milliliters of 87.. percent. formic. acid. was heated under refluxfor one hour, :CIOOIed, and the dimethyl maleate .Jadduct. ofdehydroergosteryl formate filtered. therefrom. Upon crystallization fromacetone, the purifiedimaterial meltedat 177.5 to 178.5:degreescentigrade.

Preparation 4.M-aleic acid addact of dehydro ergosterol A solution of2.0 grams of sodium hydroxide in twenty milliliters-of water was addedto a solution-o'f 1173 grams of the maleic anhydride adduct ofdehydroergosterylacetate. (M. P. 230-232 degrees centigrade) in fortymilliliters of dioxane. The mixture solidified, but dissolved onaddition of 300 milliliters of water and. heating to eighty degreescentigrade; After half an hour the solution was cooled andmade acid'withaqueous three normal hydrochloricacid, to give 1.61 grams ofprecipitate; On crystallization from a 'dioxane-water mixture, themaleic acid adduct of dehydroergosterol melted at. 190-192 degreescentigrade.

Preparation. .-'Maleic anhydride. adduct 3-'heptano'ylozty-dehydroergosterol Thenmaleic acid. adduct "ofdehydroergosterol from Preparations waszdissolvedin. a mixture ofseven'milliliters oi warm pyridineand fourteen millilitersv of lheptylicanhydride,v and. the mixture heated' under reflux: for one hour. Abouteighty percent Ofl the reaction solvent was 'removed under reducedpressure, and the residue then dissolved in methyl alcohol. The methylalcohol solution was concentrated and cooled to yield 418 grams of .themaleic/anhydride adduct of S-heytanoyloxydehydroergosterol, melting at180-19115 degrees centigrade.

Preparation 6. M'aleic anhydride. addact of- 3-'heta-acetowybisnor-5,7;9(11) -cholatrien-22-al 7 1A. solutionof.'.5.35r;grams -.of the maleic anhydride adduct of3'-beta-acetoxydehydroergosterol in 107 milliliters. of methylenechloride was cooled to about minusjseventy degrees centigrade andozonized until 505 milligrams of ozone had been absorbed. Thetemperatureof the solution was then gradually raised to about plus tento fifteen degrees centigrade, whereupon seventy milliliters of glacialacetic acid was added and the-methylene chloride removed under reducedpressure; Seven grams of zinc dust was then added to'the coldsolutionata uniform rate over a period of ten-minuteswhile keeping the reactiontemperature below plus twenty degrees cent'igrade; After beingstirredfor fifteen minutes;..the :mi-xture; was filtered and thefiltrate poured into water; There wasthus obtained 4.31 grams of. maleicanhydride adduct of 3-betaacetoxybisnor-5 ,7,9(11')--cholatrien-22-al, afine whitepowder which melted at 187-197 deg-recs centigrade.

Tor-2a, solution-10f: 0*.30 gram .of'the maleic anhydride adduct of 3beta acetoxybisncr- 5,7,9(11)-cho1atrien-22-al, in thirty milliliters ofethanol, was added twenty milliliters of alcohol containing onepercent'-2,4-dinitrophenylhydrazine and three percent concentrated hydrochloricacid. The mixture wastallowed' to stand for one hourv at roomtemperature andzxthenxplaced in a refrigerator toeomplete. precipitationof the yellowrcrystals .v The precipitate was thencollectedandarecrystallized from a mixture of l chloroform and" alcohol, to:give. the :2A-dinitrophenylhydrazone ofthemalei'c' anhydride'adductof3- milligrams of ozone per minute).

10* beta-acetoxybisnor-5 7,9(11) -cholatrien 22 al, melting at 269-271-degreescentigrade.

Preparation 7.-Malez'c anhydride adduct 0 3- beta-acetomybz'snor-5,7,9(.11) -choZatrien-22-al A two-liter, round-bottom flask was charged withfifty grams (0.93 mole) of dehydroergosteryl acetate maleic anhydrideadduct and oneliter of methylene chloride. The solution was cooled todry-ice temperature with a .trichloroethylene bath and ozonized oxygenpassed through at a rate of 1200 milliliters of oxygen per minute (atthis rate the ozonizer was producing about 36 'An additional 200milliliters of acetic acid was added and the ozonide decomposed by theaddition of fifty grams of zinc dust. The zinc dust was added inportions over a period of twenty to thirty minutes while the solutionwas stirred and the temperature maintained at seventeen to twentydegrees centigrade. After addition, the mixture was stirred for anothertwenty minutes and then filtered. The precipitated zinc dust was washedby filtering milliliters of acetic acidtherethrough, and the filtrategradually diluted with water 1 (1100110 1200 milliliters) until theproduct had been drowned out. The product was then cooled in therefrigerator overnight and filtered. The yield of crystalline productwas 42 grams, assaying 89-95 percent of the desired aldehyde.

Preparation 8 In a manneressentially that. described in. Preparation 6,the following compounds were prepared.

(1') Maleic anhydrideadduct of 3-beta-formoxybisnor-5,7,9(11)-cholatrien-22 al, melting at 95-430 degrees centigrade.2,4-dinitrophenylhydrazone, melting'at'1'65-168 degrees centigrade.

(2) Maleic anhydride ad'duct of 3-beta=heptanoyloxybisnor-5,7,9(1'1)-cholatrien 22-al, melting at'197.5-199-degrees centigrade.ZA-dinitrophenylhydrazone, melting at 253-257 degrees centigrade.

(3') Dimethyl maleate 'adduct of 3.-.beta-benzoyloxybisnor-5,7,9 1 1)-cholatrien-22-'al, melting.

at 183-187 degreescentigrade. 2,4-dinitrophenylhydrazone,melting'at224-2'49'degrees centigrade.

(4) Dimethyl maleate .a'dduct of B-beta-acetoxybisnor-5,7,9(11)--cholatrien-22-al, melting at 172-178 degrees centigrade.2,4-dinitrophenylhydrazone, melting at 238 to 244 degrees centigrade;

(5) Dimethyl maleate adductof .3-hydroxybisnor-5','7,'9(1.1)-cholatr-ien-22'-al; melting-at 16-3- degrees centigrade.2,4-dinitrophenylhydrazone,.melting at 250-254 degrees centigrade.

. In a mannensirnilar to'the-abovepthe maleic anhydride adduct of 3-hydroxybisnor-.5,7;9(11)- cholatrien-22-al is obtained fromdehydroergosteryl maleic anhydride adduct; the maleicacid adduct' of3-'hydroxybisnor-5,7',9.(11)-cholatrien- 22-al is obtained fromdehydroergosteryl maleic acid adduct; I and -3 acyloxybisnor-5,7,9(l1-)The flow' of 11 cholatrien-22-al maleic acid adducts are obtained fromthe maleic acid adduct of a 3-acyloxydehydroergosterols.

Preparation 9.-Dimethyl maleate adduct of 3- hydroaybisnor-5,7,9 (11)-choZatrien-22-al A solution of 2.69 grams (.005 mole) of the dimethylester of the maleic acid adduct of dehydroergosterol, in eightymilliliters of methylene chloride, cooled by a dry-ice andtrichloroethylene bath, was treated with ozonized oxygen until 247milligrams (.0051 mole) of ozone was absorbed. The solution was thenallowed to warm to room temperature, whereafter thirty milliliters ofacetic acid was added and the methylene chloride removed in vacuo. Whilecooling in a Water-bath at fifteen degrees centigrade, four grams ofzinc dust was added in portions with stirring, the temperature beingmaintained between fifteen and twenty degrees centigrade.

Stirring was continued for another fifteen min-;

utes, whereafter the zinc was separated by filtration. The filtrate wasdiluted with water to cloudiness, extracted with ether, the etherextract washed with sodium bicarbonate and then with water toneutrality, the solution then dried over sodium sulfate and evaporatedto dryness in vacuo. The residue was crystallized from acetic acid andwater, giving 1.92 grams (81.5 percent of the theoretical), meltingpoint 91-97 degrees centigrade, which yielded a dinitrophenylhydrazonederivative in 72.5 percent yield, melting point 212 -238 degreescentigrade. The aldehyde was recrystallized and found to have a purifiedmelting point of 163470 degrees centigrade, while thedinitrophenylhydrazone derivative was recrystallized until a meltingpoint of 250-254 degrees centigrade was attained.

Preparation 10.The maleic anhydride adduct'3-beta-acetoxy-22-acetomybisnor-5,7,9 (11) 20(22) -cholatetraene Amixture of twenty grams of the maleic anhydride adduct of3-beta-acetoxybisnor-5,7,9(11) cholatrien-22-al, six grams of anhydroussodium acetate, and 600 milliliters of acetic anhydride, was heatedunder reflux for six hours, whereafter volatile components were removedunder reduced pressure. The resulting solid was digested with fivefifty-milliliter portions of boiling acetone for five minutes each, andthe extracts combined and diluted with 130 milliliters of water. Therewas thus obtained sixteen grams of th maleic anhydride adduct of3-beta-acetoxy-22-acetoxybisnor-5,7,9 (11) ,20 (22) -cholatetraene,which melted at 186 to 193 degrees centigrade. Recrystallization of thecrude product from a mixture of acetone and pentane raised the meltingpoint to 200.5 to 202 degrees centigrade.

Preparation 11 In a manner essentially that described in Preparation 10,the following compounds were prepared:

(1) The dimethyl maleate adduct of 3-betabenzoyloxy 22acetoxybisnor-5,7,9(11) ,20(22) cholatetraene, which melted at 210 to211 degrees centigrade.

(2) The dimethyl maleate adduct of 3-betaacetoxy 22 acetoxybisnor5,7,9(11),20(22)- cholatetraene, which melted at 181 to 183 degreescentigrade.

In the same manner as given above, zz-acyloxy. e. g., formoxy, acetoxy,propionoxy, butyroXy. valeroxy, hexanoyloxy, heptanoyloxy, octanoyloxy,benzoyloxy, naphthoyloxy and the like 3-acyloxybisnor 5,7,9(11) ,20(22)cholatetraene adducts, are obtained from the compounds of Preparations6, '7, and 8. Such representative compounds include3-formoxy-22acetoxybisnor- 5,7,9 11) ,20 (22) -cholatetraene,3-propionoxy-22- acetoxybisnor 5,7,9(11),20(22) cholatetraene,3,22-dipropionoxybisnor 5,7,9 (11) ,20 (22) -cholatetraene, 3,22dibenzoyloxybisnor 5,7,9(11), 20(22)-cholatetraene, and3-heptanoyloxy-22- octanoyloxy-bisnor 5,7,9(11) ,20(22) -cholatetraeneadducts with maleic anhydride or maleic acid esters such as the dimethylmaleate, diethyl maleate, dipropyl maleate, diisopropyl maleate, dibutylmaleate, dioctyl maleate, dibenzyl maleate, and the like.

Preparation 12.-MaZeic anhydride adduct 0) 3-beta-acetoazy-5,7,9 (11-pregnatrien-20-one A solution of 5.08 grams of the maleic anhydrideadduct of 3-beta-acetoxybisnor-5,7,9(11) cholatrien-22-al enol acetatein milliliters of methylene chloride was cooled to about minus seventydegrees centigrade and ozonized until 483 milligrams of ozone had beenabsorbed. Fifty milliliters of glacial acetic acid was then added andthe methylene chloride removed under reduced pressure. An additionalthirty milliliters of glacial acetic acid was then added and the ozonidedecomposed by adding seven grams of powdered zinc at a substantiallyuniform rate while maintaining the reaction temperature betweenseventeen and twenty degrees centigrade. The mixture was stirred for anadditional twenty minutes, filtered, and the zinc washed withmilliliters of glacial acetic acid. The organic extracts were combinedand diluted with seventy milliliters of water. When crystallizationcommenced, the rate of precipitation was increased by addition of twovolumes of water. There was thus obtained 4.0 grams of the maleicanhydride adduct of 3-beta-acetoxy-5,7 ,9 11) -pregnatrien- 20-one,which melted at 240 to 264.5 degrees centigrade. Severalrecrystallizations of the crude material from acetone raised the meltingpoint to 263.5 to 264.5 degrees centigrade.

Preparation 13.-Dimethyl maleate of 3-betaacetowy-5,7,9 (11)-pregnatrien-20one A suspension of fifteen grams of3-beta-acetoxy-5,'7,9(11)-pregnatrien-20one maleic anhydride adduct in320 milliliters of methanol was cooled in an ice-salt bath. A boilingchip was added and the suspension treated with approximately 775milliliters of diazomethane-methylene chloride solution in100-milliliter portions over a period of three hours, all of the solidgoing into solution. At the end of this time the solution was reduced toone-half its original volume on the steam bath to remove excessdiazomethane, filtered, and concentrated to about 250 milliliters. Uponcooling, crystals of the dimethyl maleate of 3-beta-acetoxy-5,7,9 (11)-pregnatrien-20-one, melting at 204-208 degrees centigrade, weredeposited. The yield was 13.2 grams (8'? percent of theory).

Preparation 14.Dimethyl maleate of 3-beta- (rectory-5,7,9 (11)-pregnatrien-20-one A solution of 0.15 gram of the dimethyl maleateadduct of 3-beta-hydroxy-5,'7,9(11) -pregnatrien- 20-one, in 2.5milliliters of acetic anhydride and 2.5 milliliters of pyridine, washeated on the steam bath for ninety minutes, cooled to room temperature,and poured into ice-water. The resulting precipitate was collected byfiltration and found to-melt at 205-209 degrees centigrade."Recrystallization from. methanol gave the dimethyl maleate of3-beta-acetoxy-5,7,9(l1) -pregnatrien- 20-one, melting at 207-211degrees centigrade.

Analysis:

calfllllated for Cz9H3sO'1 C, 69.86; H, 7.68 Found C, 69.31; H, 7.86

By the same mannerof esterification, the following C-3 esters wereprepared: (1)' dimethyl maleate adduct of 3-betaformoxy5,7,9(11)-pregnatrien-ZO-one, melting point 223-230 degrees centigrade, and (2)the dimethyl maleate adduct of 3-beta-benzoyloxy-5,7,9(1.1)-.pregnatrien-Z O-one, melting point 250-254 degrees centigrade.

Preparation, 15.-Mal eic anhydrz'de adduct 3- beta-heptanoyl-owy-5,7,9(11) -pregnatrie n-20-one The maleic anhydride adduct-of 3beta-heptanoyloxy-5,7-,9 (11) -pregnatrien-20-one, melting point 170-171degrees centigrade, was prepared by refluxing the maleicgacid adduct of3-,betahydroxy-5,7,9 (1'1) -pregnatrien-20-o.ne with heptylic anhydrideand pyridine for a period of twenty hours, and working up the reactionproduct inthe usual manner.

Preparation 16.-Maleic acid adduct 0 '3-beta hydroxy-i? ,9 (1 1)-pregnatrien-20-one A solution of 4.52 grams (0.0100 mole) of the maleicanhydride adduct of 3-beta-acetoxy- 5,7,9(11) -pregnatrien-20-one, M; P.263-2645 degrees centigrade, in'a mixture of 100 milliliters of1,4-dioxane and 400 millilitersv of water containing four grams(0.10'mole) of sodium hydroxide was allowed to stand at room temperaturefor two and one-half hours, whereupon a small quantity of plate-likecrystals. formed. vThese were dissolved by heating the mixture toseventy degrees centigrade for one-half hour. The reaction mixture wasthen made acid with fifty milliliters of three normal hydrochloric acidand refrigerated to give a precipitate of 3.05 grams v ofneedle-likecrystals melting at 173-177'degrees centigrade.Oncrystallization from a dioxanewater mixture, the .compound melted at211-215 degrees centigrade. The melting point was found to varysomewhatwith the rate of heating.

Ana y is:

Calculated for; C25Ha20s C, '70.07";, H, 7.53 Found 1 C, 69.80; H.711?

Preparation 17.Dimethyl maleate of B-betahydroa'y-5,7",9 (11)-pregnatrien-20-one rficrystallization, thecompoundmeltedat 192-197degrees centigrade,

In the same manner as given above, other dialkyl maleates, e. g., thediethyl, dipropyl, diisopropyL; diloutyl, dioctyl, dicyclopentyl)dioyclohexyl, dibenzylnand; like maleates. of Behydroxy:

l4 5,7;9(11)epregnatrien-ZO-one are prepared from 3.-hydroxy-5,7,9 (11)-pr egnatrien-20-one maleic acid adduct and the appropriate diazoalkane,or by other equivalent esterification procedure.

Preparation 1'8."Maleic anhydride adduct'of 3- beta-hydroxy-Sjflfll-pregnatrien-20one Similarly, themaleic anhydride adduct of 3-beta-hydroxy-5,7,9 (1 1 -pregnatrien-20-one melting point about. 195degrees centigrade, was prepared by refluxing the maleicacid adduct of3-beta-hydroxy-5,7,9(11) pregnatrien 20 one with Dowtherm for eighthours. The B-hydroxymaleic anhydride-adduct is also obtained by heatingthe 3-hydroxy, maleic acid adduct to just above its melting point,,whichprocedure-causes water. to be evolved, withthe. closing of theanhydridering.

In the same manneras given above, still other5,7,9,(11).-pregnatrien+20-one adducts are 'prepared. from: thecorresponding 3,22-diacyloxybisnor 5,7,9(11),20.(22) cholatetraenemaleic a'cid,,,maleic acid anhydride, andmaleic acid di-.-ester'adducts. Such. compounds include the 3- formoxyand3-hydroxy-5,7,9(11)-pregnatrien- 20-one maleic acid, maleic acidanhydride, di-

methyl maleate, diethyl maleate, diloutyl maleate,-

dioctyl maleate, diisopropyl maleate, dibenzyl maleate, and the likeadducts; the corresponding. 3-propionoxy. butyroxy, valeroxy,hexanoyloxy, heptanoyloxy, octanoyloxy, naphthoyloxy, benzoyloxy, andsimilar 20-ketone adducts, including, for example.3-propionoxy-5,7,9(11)- pregnatrien-20-one dipropyl maleate,3-benzoylwry-5,7,9 (11) -pregnatrien-20-one dibenzoyl maleate,3-heptanoyloxy-5,7,9 (11).-pregnatrien-20-one dimethyl maleate,3-valeroyloxy-5,7,9(11)-pregnatrien-20-onevma-leic acid anhydrideadducts, and the like. I These are convertible tothe corresponding3-hydroxy compounds as indicated in the foregoing preparations,whereaf-ter the 9,11- double bond can be epoxidized, or the 3-acyl estermay be epoxidized directly and the 9,11- oxido compound then-convertedto the 3-hydroxy compound, as indicated in the-following.

Preparation 19.-Dimethyl maleate adduict of 3- beta-acetoxy- 9,1 1-oxido-5 ,7 -pregnadien-20-one One gram (0.002 mole) of the dimethylmaleate adduct of 3-betaacetoxy-5,7,9 11) -pregnatrien- 20-0ne wasdissolved in 25 milliliters of glacial acetic acid, and a, solution ofone milliliter of thirty percent hydrogen peroxide (four molarequivalents) in six milliliters of glacial acetic acid was added theretoat room temperature. The reaction mixture was heated on the steam bathfor four hours, and thereafter allowed to stand, at room. temperatureovernight. The mixture was then poured, into 300 millilitersxof water,the resulting precipitate separatedby filtration, washed with water, anddried. The yield was 810 milligrams of the oxido compound, melting. at197-206 degrees centigrade. After five. renrystallizations from methanoland acetone-hexane,.the dimethyl maleate adduct of 3-beta-acetoxy-9,11-oxido-5,7-pregnadien- 20 one melted. at2l6i-221degrees. centigrade [alphalb -l 114 degrees (in chloroform).

Analysis:

Calculated for CzaHs'aOafifl C, 67.68; H, 7.44 Found (2.67.74; H, 7.35

r 15 Preparation 20.--Maleic anhydride adduct of 3- beta-acetomy-QJI-ozcide-5,7-pregnadien-20-one Five grams (0.011 mole) of the maleicanhydride adduct of 3-beta-acteoxy5,7,9(1l)pregnatrien-ZO-one wasdissolved'in 120 milliliters of hot glacial acetic acid, the solutionthereafter cooled to room temperature, and a solution of fivemilliliters of thirty percent hydrogen peroxide (four molar equivalents)in thirty milliliters of glacial acetic acid added dropwise thereto withswirling. The reaction mixture was heated on the steam bath for threeand one-half hours, during which time the solution, which was originallyyellow, became colorless. The colorless solution was allowed to stand atroom temperature overnight, poured into about one liter of water, theresulting precipitate separated by filtration, washed with water, anddriedin a vacuum desiccator. The yield was 4.88 grams (94.8 percent),melting at 232-246 degrees centigrade. After two recrystallizations fromacetone, crystals of the maleic anhydride adduct of3-betaacetoxy-9,11-oxido-5,7-pregnadien-20-one, melting'at 240-246degrees centigrade, were obtained.

Analysis:

Calculated for C27H3zO7 C, 69.21; H, 6.89 Found C, 69.43; H, 6.94 69.30;6.97

Preparation 21.--Maleic anhydride adduct 3- betaeaceiowy- 9,1 1-oxido-5,7-preanadien-2 O-ane A solution of fifty grams of the maleicanhydride adduct of 3-beta-acetoxy-5,7,9(1l)pregnatrien-20-one in 1200milliliters of glacial acetic acid was prepared by heating theingredients together on a steam bath. The mixture was then cooled belowforty degrees centigrade and fifty milliliters of thirty percenthydrogen peroxide in 300 milliliters of glacial acetic acid addedthereto. The mixture was then heated on the steam bath for one hour at atemperature of 85 degrees centigrade or above, and was then poured intothree to five volumes of ice and water. The yield was 47.7 grams (92percent), melting point 238- 243 degrees centigrade, [alpha] +31.1degrees in chloroform. The product was dissolved in methylene chlorideand precipitated by addition of ether to give 37.7 grams of purifiedproduct having a melting point of 254 to 259 degrees centigrade, [alpha]+33.2 degrees (in chloroform) Preparation .22

Analysis:

Calculated for 0321-1340: %C, 72.43; %H, 6.46 Found %C, 72.62; %H, 6.42

(2) Maleic anhydride adduct of3-heptanoyloxy-9,11-oxido-5,7-pregnadien-20-one, M. P. 168- 169.5degrees centigrade, [alpha] +26.1 degrees (in chloroform).

Analysis:

Calculated for Cal-1410': %C,71.48; %H,7.69 Found %C,71.27; %H, 7.43

16 Preparation 23.Maleic acid adduct 03-betahydroxy-QJI-oxido-5,7-pregnadien-20-one Approximately 445milliliters of five percent sodium hydroxide solution was added to 22.26grams of 3-beta-acetoxy-9,l1oxido-5,7-pregnadien-20-one maleic anhydrideadduct in a oneliter Erlenmeyer flask, and the mixture stirred until thesolid had gone into solution. About 185 milliliters of ten percenthydrochloric acid was then added at room temperature or below, until themixture was acid to congo red paper, whereupon the hydroxy diacid beganto precipitate. Upon cooling the flask overnight, filtering andair-drying the product at room temperature, a yield of 19.4 grams ofdesired 3-beta-hydroxy- 9,11 -oxido-5,7pregnadien-20-one maleic acidadduct, melting at 229-233 degrees centigrade with decomposition, wasobtained. An additional crop of crystals was obtained by concentrationof the mother liquor.

The same compound is obtained by epoxidation of the 9,11-double bond of3-beta-hydroxy- 5,7,9(11) -pregnatrien-20-one, maleic acid adduct withhydrogen peroxide in the manner of preceding preparation 21, using aglacial acetic acid medium.

Preparation 24.-Maleic acid anhydride adduct of 3beta-hydromy-9,11-oxido-5,7-pregnadien- 20-one3-beta-hydroxy-9,11oxido-5,7-pregnadien 20 one maleic acid adduct (19.4grams) was placed in a vacuum oven and heated for ten hours at 137-140degrees centigrade under a pressure of only one-half millimeter ofmercury. The yield of desired anhydride, which melts at 233 to 240degrees centigrade with decomposition, was quantitative.

The same product is obtained by epoxidation of the 9,11-double bond of3-beta-hydroxy- 5,7,9(11)-pregnatrien20-one maleic acid anhydride adductwith hydrogen peroxide, according to the manner of preparation 21, usinga glacial acetic acid medium.

Preparation 25.-Monomethyl maleate of 3-betahydromy-SIJI-0xido-5,7-pregnadien-20-0ne A solution of five grams of the maleicanhydride adduct of 3-beta-acetoxy-9,1l-oxido-5,7-pregnadien-20-one in145 milliliters of methanol and a solution of five grams of sodiumhydroxide in 25 milliliters of water were mixed and the mixture allowedto stand for one hour, whereafter 145 milliliters of Water was added,the mixture allowed to stand for seven hours, then made acid with threenormal hydrochloric acid and placed in the refrigerator. The mixture wasthen extracted with methylene chloride, washed with sodium chloridesolution, and dried over sodium sulfate. The yield was 4.93 grams,melting point -160 degrees centigrade. After recrystallization threetimes from a solution of chloroform, methanol, and ether, the meltingpoint was 193-198 degrees centigrade ialphal +19.4 degrees (chloroform).

Analysis:

Calculated for C26H34O7I C, 68.10; H, 7.47; OCHa, 6.76 Found:

% C, 67.90; H, 7.14; OCI-Ia, 6.22 67.97 7.35 6.12

The same product is obtained by epoxidation of the 9,11 double bond of3-beta-hydroxy-5,7,9- (11) -pregnatrien-20-one monomethyl maleatewith-hydrogen peroxide-according to the manner Preparation 26.Dimethylmaleate of 3-betaester of the maleic acid adduct of 3-beta-hy-.

droxy-9,11-oxido-5,7 -pregnadien--one in twenty millimetersof anhydrousether was treated with an excess of diazomethane in methylene chloridesolution. On addition of methylene chloride the compound went insolution, and was allowed to stand about two hours, the solutionevaporated to dryness, and the residue. dissolved in twelve millilitersof. hot ethanol, filtered, concentrated, water added, "and 'the solutionplaced in the refrigerator. .The precipitate. was

separated by filtration, to give a'yield of 0.5.4 gram, melting at207-211 degrees centigrade. Theproductwas passed over a column ofalumina for purification, and this procedure yielded 0.50 gram ofproduct, which upon crystallization from methanol had a melting point of210-212 degrees centigrade, [alpha] +15.4 degrees (chloroform).

Analysis:

' Calculated for C vHseOq:

C, 68.62; H, 7.68; OCI-Is, 13.13 Found:

% C, 68.62; H, 7.61; OCI-h, 12.10 68.61 7.64 12.22

Infra red analysis was in agreement with the structure proposed.

The same product is obtained by epoxidation butyl maleate adduct,3-hydroxy-9,11-oxido-5,7-

pregnadien-20-one diamyl maleate adduct,3-hydroxy-9,l1-oxido-5,7-pregnadien-20-one dihexyl maleate adduct,3-hydroxy-9,11-0xido-5,7-pregnadien-ZO-one diheptyl maleate adduct,3-hydroxy-9,11-oxido-5,7pregnadien-20-one dioctyl maleate adduct, andthe like, which are prepared in the same manner as given above, byepoxidation of the selected 9,11-unsaturated starting compound.

Example 1.Maleic anhydrz'de adduct 0 9,1i-oxido-5,7-pregnadien-3,20-dione A solution of 2.6 grams of chromiumtrioxide in 2.5 mililiters of water, 45 milliliters of acetic acid, and.9 milliliter of sulfuric acid was added dropwise with stirring to asolution of sixteen grams of the maleic anhydride adduct of3-betahydoxy-9,11-oxido-5,7-pregnadien-20-one in 120 milliliters ofacetic acid in a one-liter Erlenmeyer flask fitted with a stirrer anddropping funnel. The dropwise addition required approximately thirtyminutes, during which time the temperature of the reaction mixture wasmaintained between seventeen and nineteen degrees centigrade and thereaction mixture was constantly stirred. The cooling bath was thenremoved, the temperais ture of themixture allowed to rise to roomtemperature, and the mixture stirred for an additional fifteen minutesat that temperature. Two milliliters of methanol was then added,followed by 600 milliliters of water, which was added slowly withstirring by means of a dropping funnel.

The addition of water required about forty minutes, whereafter theflask' was cooled and the product filtered and washed with water. Theyield of desired maleic 'anhydride adduct. of9,11-oxido-5,7-pregnadien-3,20-dione was" 12.34 grams (77 percent),havinga melting point'with decomposition of 248-256 degrees centigrade.

Example 2.JJcleic acid adduct of 9,11-oan'do- 5,7;-p7;eg;nadien-3,20-dione A solution of 0,20 gram. of chromium trioxide in0.1 milliliter of water and ten milliliters of acetic acid was addedinportions over a period of one hour to a solution of 1.20 gram of themaleic acid adductof 3 o'eta-hydroxy-9dl-oxido-5,7-pregnadien-20,-one in24 milliliters of glacial acetic acid at room temperature. The solution,upon standing for45 minutes, became completely green, and was. dilutedwith water and then concentrated in vacuo to a heavy syrup. This wasmixed with 100. milliliters of aqueous sodium chloride containing threemilliliters of three normal hydrochloric acid. A light green, gummyprecipitate formed upon cooling for 24 hours. This was separated.byfiltration, and the filtrate allowed to stand another 24 hours in therefrigerator, giving 0.42 grams of white crystals melting at 262-270degrees centigrade. The crystalline precipitate was dissolved in fifteenmilliliters of one percent aqueous sodium hydroxide and made acid with1.5 milliliters of three normal hydrochloric acid to give a clearsolution which, on standing, deposited analmost quantitative yield ofcrystals melting at268 272 degrees centigrade.

Example 3.Dz'methy l maleate adduct of 9,11-

oxida-5,7-predn dien 3,20-dione An excess of diazomethane in methylenechloride was added to a suspension. of 116 milligrams of the maleic acidadduct of 9,11-oxido-5,7-pregnadien-3,20-dione in three milliliters ofmethanol. After two hours, the reaction mixture was evaporated todryness 0n the steam bath. The product was dissolved in five millilitersof benzene and chromatographed over alumina, giving 65.8 milligrams ofthe crystalline dimethyl ester, M. P. 215-220 degrees centigrade aftercrystallization from methanol-water.

The identical product is obtained by the oxidation of the dimethylmaleate adduct of 3-beta-hydroxy-9,11-oxido-5,7-pregnadien-20-oneaccording to the manner of Example 1.

In the same manner, other dialkyl maleate adducts of9,11-oxido-5,7-pregnadien-3,20-dione are prepared from the correspondingdialkyl maleate of the 3-hydroxy compound. Such compounds include, forexample, the 9,11-oxido-5,7- pregnadien-3,20-dione dimethyl, diethyl,dipropyl, diisopropyl, dibutyl, diamyl, dihexyl, diheptyl, and dioctylmaleate adducts.

In the same manner as given for the preparation of9,11-oxido-5,7-pregnadien-3,20-dione maleic anhydride adducts, thecorresponding maleimide and N-alkylmaleimide adducts are prepared fromthe corresponding 9,11-unsaturated compounds.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. A 9,11-oxido-5,'7-pregnadien-3,20-dione adduct represented by theformula:

Oils

wherein A is an adduct radical of a dienophile selected from the groupconsisting of maleic acid, maleic acid anhydride, and maleic aciddiesters wherein the esterifying groups contain up to and includingeight carbon atoms, to convert the 3- hydroxy group to a 3-keto group,said oxidation being conducted by mixing the starting adduct with fromone to four molar equivalents of chromic acid in an acetic acid medium,in the presence of a catalytic quantity of sulfuric acid, at atemperature of about sixteen to twenty-six degrees centigrade, andrecovering the 3-keto adduct from the reaction product.

6. The process of claim 5, wherein the starting adduct is3-hydroxy-9,11-oxido-5,7-pregnadien- 20-one maleic anhydride adduct.

7. The process of claim 5, wherein the starting adduct is3-hydroxy-9,11-oxido-5,7-pregnadien-20-one maleic acid adduct.-

8. The process of claim 5, wherein the starting adduct is3-hydroXy-9,11-oxido-5,7-pregnadien-20-one dialkyl maleate adduct.

9. The process of claim 5, wherein the starting adduct is3-hydroxy-9,11-oxido-5,'I-pregnadien-20-one dimethyl maleate adduct.

ROBERT H. LEVIN. A VERN McINTOSH, JR. GEORGE'B. SPERO.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Serini Apr. 29, 1941 OTHER REFERENCESNumber

1. A 9,11-OXIDO-5,7-PREGNADIEN-3,20-DIONE ADDUCT REPRESENTED BY THEFORMULA: